2-CHLORO-3-FLUOROPYRIDINE-4-BORONIC ACID

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.8 g (4.1 mmol) of 2-bromoimidazo[1,2-a]pyridine, 0.8 g (4.2 mmol) of 4-chloro-2-fluoro-5-methoxyphenylboronic acid, and 0.2 g (0.28 mmol) of bis(triphenylphosphine)palladium(II) chloride were heated in 30 ml of glyme at reflux for 2 h. The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water and the separated organic layer washed with brine and dried over magnesium sulfate. On evaporating in vacuo, the remaining residue was flash chromatographed on silice gel (1:1 hexane/ethyl acetate) to afford 0.7 g of the title compound (m.p. 139-141° C.). NMR (CDCl3, 400 MHz); δ4.03 (s, 3H), 6.81 (t, 1H), 7.21 (m, 2H), 8.63 (d, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H). at reflux for 2 h The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water the separated organic layer washed with brine dried over magnesium sulfate On evaporating in vacuo chromatographed on silice gel (1:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.8 g (4.1 mmol) of 2-bromoimidazo[1,2-a]pyridine, 0.8 g (4.2 mmol) of 4-chloro-2-fluoro-5-methoxyphenylboronic acid, and 0.2 g (0.28 mmol) of bis(triphenylphosphine)palladium(II) chloride were heated in 30 ml of glyme at reflux for 2 h. The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water and the separated organic layer washed with brine and dried over magnesium sulfate. On evaporating in vacuo, the remaining residue was flash chromatographed on silice gel (1:1 hexane/ethyl acetate) to afford 0.7 g of the title compound (m.p. 139-141° C.). NMR (CDCl3, 400 MHz); δ4.03 (s, 3H), 6.81 (t, 1H), 7.21 (m, 2H), 8.63 (d, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H). at reflux for 2 h The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water the separated organic layer washed with brine dried over magnesium sulfate On evaporating in vacuo chromatographed on silice gel (1:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at −78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below −69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280-296° C.). the temperature below −69° C. the reaction mixture stirred 3 h the resulting biphase system stirred 1 h The separated aqueous phase was separated washed with an additional 30 ml of diethyl ether Combined organic layers were washed with brine dried over magnesium sulfate Evaporating in vacuo gave a white solid which filtered dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at −78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below −69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280-296° C.). the temperature below −69° C. the reaction mixture stirred 3 h the resulting biphase system stirred 1 h The separated aqueous phase was separated washed with an additional 30 ml of diethyl ether Combined organic layers were washed with brine dried over magnesium sulfate Evaporating in vacuo gave a white solid which filtered dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.8 g (4.1 mmol) of 2-bromoimidazo[1,2-a]pyridine, 0.8 g (4.2 mmol) of 4-chloro-2-fluoro-5-methoxyphenylboronic acid, and 0.2 g (0.28 mmol) of bis(triphenylphosphine)palladium(II) chloride were heated in 30 ml of glyme at reflux for 2 h. The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water and the separated organic layer washed with brine and dried over magnesium sulfate. On evaporating in vacuo, the remaining residue was flash chromatographed on silice gel (1:1 hexane/ethyl acetate) to afford 0.7 g of the title compound (m.p. 139-141° C.). NMR (CDCl3, 400 MHz); δ4.03 (s, 3H), 6.81 (t, 1H), 7.21 (m, 2H), 8.63 (d, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H). at reflux for 2 h The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water the separated organic layer washed with brine dried over magnesium sulfate On evaporating in vacuo chromatographed on silice gel (1:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at −78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below −69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280-296° C.). the temperature below −69° C. the reaction mixture stirred 3 h the resulting biphase system stirred 1 h The separated aqueous phase was separated washed with an additional 30 ml of diethyl ether Combined organic layers were washed with brine dried over magnesium sulfate Evaporating in vacuo gave a white solid which filtered dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at −78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below −69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280-296° C.). the temperature below −69° C. the reaction mixture stirred 3 h the resulting biphase system stirred 1 h The separated aqueous phase was separated washed with an additional 30 ml of diethyl ether Combined organic layers were washed with brine dried over magnesium sulfate Evaporating in vacuo gave a white solid which filtered dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a preparation similar to that described above for 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine, reaction of 8.9 g (41 mmol) of 2,3-dichloro-5-trifluoromethylpyridine and 7.9 g (41 mmol) of 4-chloro-2-fluoro-5-methoxybenzeneboronic acid and subsequent purification of the crude product by chromatography on silica gel (methylene chloride as eluent) resulted in 2.6 g of colorless crystals. In a preparation similar to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.8 g (4.1 mmol) of 2-bromoimidazo[1,2-a]pyridine, 0.8 g (4.2 mmol) of 4-chloro-2-fluoro-5-methoxyphenylboronic acid, and 0.2 g (0.28 mmol) of bis(triphenylphosphine)palladium(II) chloride were heated in 30 ml of glyme at reflux for 2 h. The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water and the separated organic layer washed with brine and dried over magnesium sulfate. On evaporating in vacuo, the remaining residue was flash chromatographed on silice gel (1:1 hexane/ethyl acetate) to afford 0.7 g of the title compound (m.p. 139-141° C.). NMR (CDCl3, 400 MHz): δ 4.03 (s, 3H), 6.81 (t, 1H), 7.21 (m, 2H), 8.63 (d, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H). at reflux for 2 h The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water the separated organic layer washed with brine dried over magnesium sulfate On evaporating in vacuo chromatographed on silice gel (1:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at -78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below -69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280-290° C.). the temperature below -69° C. the reaction mixture stirred 3 h the resulting biphase system stirred 1 h The separated aqueous phase was separated washed with an additional 30 ml of diethyl ether Combined organic layers were washed with brine dried over magnesium sulfate Evaporating in vacuo gave a white solid which filtered dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.8 g (4.1 mmol) of 2-bromoimidazo[1,2-a]pyridine, 0.8 g (4.2 mmol) of 4-chloro-2-fluoro-5-methoxyphenylboronic acid, and 0.2 g (0.28 mmol) of bis(triphenylphosphine)palladium(II) chloride were heated in 30 ml of glyme at reflux for 2 h. The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water and the separated organic layer washed with brine and dried over magnesium sulfate. On evaporating in vacuo, the remaining residue was flash chromatographed on silice gel (1:1 hexane/ethyl acetate) to afford 0.7 g of the title compound (m.p. 139°-141° C.). NMR (CDCl3, 400 MHz): δ4.03 (s, 3H), 6.81 (t, 1H), 7.21 (m, 2H), 8.63 (d, 1H), 7.92 (d, 1H), 8.04 (s, 1H), 8.14 (d, 1H). at reflux for 2 h The reaction mixture was partitioned between 250 ml of ethyl acetate and 100 ml of water the separated organic layer washed with brine dried over magnesium sulfate On evaporating in vacuo chromatographed on silice gel (1:1 hexane/ethyl acetate)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 2.0 g (7.0 mmol) of 2-chloro-4-fluoro-5-iodo-anisole (made from the compound of Example 11, Step A by methylation) stirring in 30 ml of diethyl ether at -78° C., 4.8 ml (7.7 mmol) of 1.6M n-butyl lithium was added dropwise (keeping the temperature below -69° C.). After stirring 0.5 h, 0.91 ml (8.0 mmol) of trimethyl borate in 15 ml of diethyl ether was added dropwise and the reaction mixture stirred 3 h before allowing to warm to room temperature. Slowly, 1N aqueous hydrogen chloride was added and the resulting biphase system stirred 1 h. The separated aqueous phase was separated and washed with an additional 30 ml of diethyl ether. Combined organic layers were washed with brine and dried over magnesium sulfate. Evaporating in vacuo gave a white solid which was suspended in hexane, filtered, and dried to afford 0.86 g of a technical sample of 4-chloro-2-fluoro-5-methoxyphenylboronic acid (m.p. 280°-290° C.). the temperature below -69° C. the reaction mixture stirred 3 h the resulting biphase system stirred 1 h The separated aqueous phase was separated washed with an additional 30 ml of diethyl ether Combined organic layers were washed with brine dried over magnesium sulfate Evaporating in vacuo gave a white solid which filtered dried